The mortality from pancreatic cancer coincides closely with its incidence, indicating a dismal outlook. Hereditary factors probably account for approximately 5%-10% of the pancreatic cancer burden. The molecular genetic etiology of pancreatic cancer is only beginning to be identified. We describe our genetic counseling experience with 2 large families prone to pancreatic cancer-malignant melanoma in which p16 (CDKN2) germline mutations had been identified. Members of each family underwent intensive counseling before and at the time of disclosure of p16 germline mutation findings. Two non-cancer-affected siblings from each of the 2 families had p16 mutations identified in DNA from their peripheral blood lymphocytes. In each case, a parent affected with pancreatic cancer also harbored the p16 mutation identified in DNA from their respective tumor blocks. The sibling pairs stated that they would seriously consider prophylactic pancreatectomy if biomarkers or imaging findings suggested a precancerous state. Our experience highlights limited options for managing these families and emphasizes the need for better tools to diagnose pancreatic cancer at a curable stage.